Interstitial cystitis (IC) is an irritable bladder syndrome diagnosed clinically by a symptom complex typified by chronic, unexplained irritative voiding symptoms; sterile urine; and specific findings in the bladder mucosa on cystoscopy. Numerous causes of IC have been suggested; however, convincing evidence supporting an etiology is lacking. It is our hypothesis that IC results from an aberrant mucosal immune response. Under normal conditions, mucosal immunity in the bladder is regulated to respond to invasion with an immunoglobulin predominated response. In IC, a deviant regulatory process allows the induction of a predominately cell- mediated immune response which is characteristic of IC. We demonstrate herein that antigens instilled into normal bladders are internalized and induce inflammation consistent with that observed in IC. Bacterial lipopolysaccharide appears to modulate the internalization process. It is our hypothesis that the epithelium and/or associated cells function as sentinel cells that signal the immune system of impending invasion. These signals (cytokines) recruit inflammatory cells that respond to the challenge (antigens in the urine). Thus, IC could result from either sequelae of a normal response to invasion or from an inappropriately induced response. The studies outlined in this application propose to examine the mechanisms by which antigens are allowed entrance through a normal bladder epithelium, and to identify the immunologic events associated with the induction and maintenance of the observed inflammatory response. To this end experiments are planned to trace the localization and movement of urine antigen in the bladder. This will be accomplished by immunohistochemistry, autoradiography, and electron microscopy. Also, the development of the immune response will be characterized by in vitro studies determining the effect of bladder antigen presenting cells on the development of T helper cell subsets (TH1 & TH2). The influence of LPS on antigen internalization and T cell response development also will be determined. The role of cytokines in antigen transport and T cell response development will be determined in vivo using reverse transcription of cytokine mRNA and polymerase chain reaction.